Throughout the last decade, the use of bioluminescence reporter systems has seen an exponential growth in research applications. As a result, bioluminescence imaging (BLI) has become an indispensible component of molecular imaging at Washington University and throughout the world. The use of multiple imaging modalities to address biological questions is now commonplace in imaging research laboratories. In a new twist on BLI, Robertson et al. (Phys Med Biol 2009) showed that the IVIS 100 and 200 BLI scanners (which have now been replaced by the IVIS Lumina and Spectrum, respectively) could consistently detect a Cerenkov light signal from 18F and 13N nuclides. Cerenkov radiation is produced when a charged particle travels with a velocity that exceeds the speed of light through an insulating medium. Cerenkov radiation is produced in a continuous spectrum from the near ultraviolet through the visible spectrum, distributed inversely proportional to the squire of the wavelength. "Cerenkov luminescence imaging" (CLI) was described for in vivo imaging of mice with radiopharmaceuticals that emit either positron or beta minus, and demonstrated a good correlation with 18FDG PET in detecting a subcutaneous tumor implant. Independently, another group of researchers (Liu et al, PLoS One 2010) validated CLI with additional positron and beta minus emitters. We propose the purchase of an IVIS Lumina II XR (Caliper Life Sciences, Inc.), a new generation molecular imaging tool capable of detecting luminescence, fluorescence, and x-ray emissions. The introduction of concomitant x-ray imaging with bioluminescence provides an additional degree of resolution by putting the bioluminescence signal in anatomical context. Our intended use of the IVIS Lumina II XR can be separated into three general categories: 1) projects that involve CLI;2) projects that involve BLI and fluorescence imaging for monitoring targeted radiotherapy with beta emitting radiopharmaceuticals;and 3) traditional BLI experiments. The CLI applications will focus on developing high throughput assessment of novel PET radiopharmaceuticals. Washington University has the ideal faculty and resources to more fully develop the new CLI technology. We have 8 NIH-funded users developing radiopharmaceuticals and multimodality imaging agents, and one of them (Dr. Tai) develops PET/optical instrumentation. The existing faculty, facilities and resources at WU, together with strong institutional support, will ensure that the IVIS Lumina II XR will be utilized and developed further for a new, cutting-edge technology, which will benefit WU as a university, as well as the imaging community as a whole. Public Health Relevance: Molecular imaging is a science involving non-invasive imaging of molecular processes. We propose to purchase an IVIS Lumina II XR (Caliper Life Sciences, Inc.), a new generation molecular imaging tool capable of detecting luminescence, fluorescence, and x-ray emissions. Washington University will use the instrument primarily for "Cerenkov luminescence imaging" a cutting-edge technology designed for high throughput radiopharmaceutical development.